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Background and Aims: Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH. Methods: Groups of 12-week-old ApoE-/- mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD). After 3 weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100 mg/kg body weight) or vehicle (0.5% carmellose) every day, 5 days/week for a further 4 weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed. Results: IFM-514 inhibited IL-1β production in mice challenged with 20 mg/kg lipopolysaccharide, and in mouse and human inflammatory cells in vitro. IFM-514 inhibited hepatic inflammation in the in vivo non-alcoholic steatohepatitis model assessed by H&E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious in vivo in MDC-fed ApoE-/- mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed ApoE-/- mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached. Conclusion: Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.
Background: The prevalence of metabolic liver diseases is increasing and approved pharmacological treatments are still missing. Many animal models of nonalcoholic fatty liver disease (NAFLD) show a full spectrum of fibrosis, inflammation and steatosis, which does not reflect the human situation since only up to one third of the patients develop fibrosis and nonalcoholic steatohepatitis (NASH). Methods: Seven week old C57Bl/J mice were treated with ethanol, Western diet (WD) or both. The animals’ liver phenotypes were determined through histology, immunohistochemistry, Western blotting, hepatic triglyceride content and gene expression levels. In a human cohort of 80 patients stratified by current alcohol misuse and body mass index, liver histology and gene expression analysis were performed. Results: WD diet and ethanol-treated animals showed severe steatosis, with high hepatic triglyceride content and upregulation of fatty acid synthesis. Mild fibrosis was revealed using Sirius-red stains and gene expression levels of collagen. Inflammation was detected using histology, immunohistochemistry and upregulation of proinflammatory genes. The human cohort of obese drinkers showed similar upregulation in genes related to steatosis, fibrosis and inflammation. Conclusions: We provide a novel murine model for early-stage fatty liver disease suitable for drug testing and investigation of pathophysiology.
Background and Purpose: Activation of hepatic thyroid hormone receptor β (THR-β) is associated with systemic lipid lowering, increased bile acid synthesis, and fat oxidation. In patients with non-alcoholic steatohepatitis (NASH), treatment with THR-β agonists decreased hepatic steatosis and circulating lipids, and induced resolution of NASH. We chose resmetirom (MGL-3196), a liver-directed, selective THR-β agonist, as a prototype to investigate the effects of THR-β activation in mice with diet-induced obesity (DIO) and biopsy-confirmed advanced NASH with fibrosis.
Experimental Approach: C57Bl/6J mice were fed a diet high in fat, fructose, and cholesterol for 34 weeks, and only biopsy-confirmed DIO-NASH mice with fibrosis were included. Resmetirom was administered at a daily dose of 3 mg·kg−1 p.o., for 8 weeks. Systemic and hepatic metabolic parameters, histological non-alcoholic fatty liver disease (NAFLD) activity and fibrosis scores, and liver RNA expression profiles were determined to assess the effect of THR-β activation.
Key Results: Treatment with resmetirom did not influence body weight but led to significant reduction in liver weight, hepatic steatosis, plasma alanine aminotransferase activity, liver and plasma cholesterol, and blood glucose. These metabolic effects translated into significant improvement in NAFLD activity score. Moreover, a lower content of α-smooth muscle actin and down-regulation of genes involved in fibrogenesis indicated a decrease in hepatic fibrosis.
Conclusion and Implications: Our model robustly reflected clinical observations of body weight-independent improvements in systemic and hepatic metabolism including anti-steatotic activity.